What is the role of sacubitryl (valsartan)/sacubitril in treating right ventricle failure, particularly in patients with a history of heart failure, hypertension, or impaired renal function?

Sacubitril/Valsartan in Right Ventricular Failure

Sacubitril/valsartan should be considered in patients with systemic right ventricular failure, as emerging evidence demonstrates improved RV systolic function, reverse remodeling, and clinical status, though it is not yet formally guideline-endorsed for this specific indication. 1

Evidence for Systemic Right Ventricular Failure

The most compelling data comes from a prospective study of 50 patients with systemic right ventricles (transposition of great arteries post-Senning/Mustard or congenitally corrected transposition) showing:

• Significant improvement in RV systolic function: 3D echocardiography demonstrated RV ejection fraction increased from 35.6±8.1% to 41.5±7.5% (p<0.001) at one year 1
• Reverse remodeling: End-diastolic volume decreased from 181±63 mL to 156±50 mL and end-systolic volume from 117±48 mL to 89±33 mL (both p≤0.002) 1
• Improved strain parameters: RV global longitudinal strain improved from -13.9% to -15.3% and free-wall strain from -14.3% to -17.2% (both p<0.001) 1
• Clinical improvement: NYHA class improved (p<0.001), 6-minute walk distance increased from 425m to 500m (p<0.001), and quality of life improved 1
• Good tolerability: Only 4% discontinued due to hypotension and 2% developed nephrotic syndrome, with no major adverse events 1

Mechanism of Benefit in RV Failure

Sacubitril/valsartan works through dual mechanisms that are theoretically beneficial for RV dysfunction:

• Neprilysin inhibition increases natriuretic peptides (ANP, BNP, CNP), bradykinin, and adrenomedullin, promoting vasodilation and natriuresis 2
• Angiotensin II receptor blockade prevents RAS-mediated vasoconstriction and maladaptive remodeling 2
• These combined effects reduce RV afterload (particularly important in pulmonary hypertension contexts) and promote favorable ventricular remodeling 1

Dosing and Initiation in RV Failure

Start with 24/26 mg twice daily in patients with systemic RV failure, particularly if there is:

• Borderline blood pressure 3
• Renal impairment (eGFR <30 mL/min/1.73m²) 4
• Age ≥75 years 5

Titrate every 2-4 weeks to target dose of 97/103 mg twice daily as tolerated 3, 6. In the systemic RV study, only 42% reached target dose, yet significant benefits were observed even at submaximal doses 1.

Critical Safety Considerations

Mandatory Precautions:

• 36-hour washout from ACE inhibitors to avoid angioedema risk 3, 6
• Monitor blood pressure closely: Systolic BP decreased by ~7 mmHg and diastolic by ~7 mmHg in the systemic RV cohort 1
• Monitor renal function: Check creatinine and potassium within 1-2 weeks after initiation and with each dose increase 5
• Contraindicated with history of angioedema related to prior ACE-I/ARB therapy 3

Common Pitfalls:

• Do not discontinue for asymptomatic hypotension alone, as mortality benefits persist even with lower BP 6
• Renal function requires close surveillance, particularly in complex congenital heart disease where creatinine may increase 7
• Target dose may not be achievable in all patients, but submaximal doses still provide clinical benefit 6, 1

Comparison with Standard Left Ventricular Heart Failure

While sacubitril/valsartan has Class I guideline recommendations for HFrEF (left ventricular EF <40%) based on PARADIGM-HF showing 20% reduction in cardiovascular death and 21% reduction in HF hospitalization 2, 3, data for isolated RV failure remains limited to smaller studies 1, 7, 8.

Divergent Evidence:

• Positive data: The 2023 prospective study showed clear functional and structural benefits in systemic RV 1
• Mixed results: A 2020 retrospective series of 23 complex ACHD patients showed no improvement in ventricular function or NYHA class, with increased creatinine and 5 patients discontinuing therapy 7
• Small case series: A 2020 Australian series of 5 ACHD patients reported mean improvement of one NYHA functional class at 6 months 8

The discrepancy likely reflects differences in patient selection, underlying anatomy complexity, and baseline hemodynamics.

Clinical Algorithm for RV Failure

Consider sacubitril/valsartan if:

1. Systemic RV with reduced systolic function (EF <40% or equivalent by strain/FAC) 1
2. NYHA class II-III symptoms despite standard therapy 1, 8
3. Elevated NT-proBNP 1
4. No contraindications (angioedema history, severe hypotension, pregnancy) 3

Prioritize in:

• Transposition of great arteries post-atrial switch (Senning/Mustard) 1
• Congenitally corrected transposition with systemic RV 1
• Patients who tolerated prior ACE-I/ARB therapy 8

Exercise caution in:

• Complex ACHD with multiple prior surgeries and severe comorbidities 7
• Baseline systolic BP <100 mmHg 1
• eGFR <30 mL/min/1.73m² (use reduced starting dose) 4

Monitoring Protocol

At initiation and each dose increase:

• Blood pressure (sitting and standing) 1
• Serum creatinine and potassium within 1-2 weeks 5
• NT-proBNP at 3-6 months 1

At 6-12 months:

• Echocardiographic assessment of RV function (FAC, strain, 3D volumes if available) 1
• NYHA functional class and 6-minute walk test 1
• Quality of life assessment 1

Special Populations

With Renal Impairment:

Sacubitril/valsartan can be used in CKD, including severe impairment, with dose adjustment 6. Start at 24/26 mg twice daily if eGFR <30 mL/min/1.73m² 4. The medication is unlikely to be removed by hemodialysis due to high protein binding 4.

With Pulmonary Hypertension:

While not specifically studied, the vasodilatory effects may theoretically benefit RV afterload in pulmonary hypertension contexts 2. However, close monitoring is essential as hypotension risk may be higher.